Elucidation of the genetic etiology of Costello Syndrome

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Costello syndrome (CS) is a multiple congenital anomaly syndrome of unknown genetic etiology whereby patients have characteristic dysmorphic features, growth failure, significant neurodevelopmental delay and a predisposition to develop early childhood cancers. The diagnosis of this genetic disorder is made solely on a clinical basis. Although the vast majority of the cases with CS have been sporadic, the inheritance of CS remains unclear and the genetic basis is unknown. Patients with CS have phenotypic overlap with other cancer syndromes, namely Noonan syndrome (NS) and neurofibromatosis-1 (NF-1). These syndromes are caused by genetic mutations that result in activation of the Ras pathway. The hypothesis of this proposal is that due to the phenotypic similarity to NS and NF-1, patients with CS have a congenital/constitutional alteration in the Ras pathway. In this project, we will take advantage of a unique cohort of patients with CS to test this hypothesis by the identification and characterization of the gene(s) for CS. This will entail continued expansion of this cohort (Aim 1). We will use a multifaceted molecular approach for gene identification, which will include scanning CS patient genomes for constitutional aberrations (Aim 2), scanning genomes of tumors from CS patients and from sporadic tumors of similar type for shared aberrations that may pinpoint the locus of the genetic defect in CS (Aim 3), functional evaluation of the Ras pathway or other candidates in CS cells (Aim 4) and sequencing of Ras pathway or other candidates (Aim 5). Identification of the CS gene will lead to the ability to molecularly diagnose patients with CS. This, in turn, will improve the clinical management of these patients. Because of the wide phenotypic effect seen in children with CS, the elucidation of the genetic etiology will not only help us gain great insight into the cause and progression of cancer, but also understand how such a gene is involved in the regulation of normal human development. In addition, we may discover that malignancies from CS patients are unique to those that arise sporadically underscoring the importance of understanding the pathogenesis of these cancers and ultimately facilitating the development of appropriate therapies. Furthermore, information gained from this study will increase our understanding of common pediatric issues such as congenital cardiac anomalies and neurodevelopmental delay.